Angiogenesis and chronic kidney disease

Abstract

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported.Further analysis of the involvement of angiogenesis-related factors in the development of CKD is required. Determining the disease stage at which therapy is most effective and developing an effective drug delivery system targeting the kidney will be essential for pro-or anti-angiogenic strategies for patients with CKD.

Figure 1

Mechanisms of action of vasohibin (VASH)-1 in diabetic nephropathy. (A) Mechanisms involved in the progression of diabetic nephropathy. (B) Exogenous VASH-1 suppresses renal alterations in the experimental mouse type 1 diabetes model through anti-angiogenic, anti-inflammatory and anti-fibrotic effects and also through protecting podocytes. VASH-1 suppresses excessive activation of VEGF-A signaling on glomerular endothelial cells, and also exerts direct effects on mesangial cells and podocytes in diabetic environments [30]. AGE = advanced glycation end-product; Ang-II = angiotensin-II; ESRD = end stage renal disease; GBM = glomerular basement membrane; MM = mesangial matrix; PKC = protein kinase C; TGF-β = transforming growth factor-β.

Figure 2

Regulation of angiogenic process by endogenous VASH-1 and VASH-2. Levels of endogenous VASH-1 are decreased in proliferating endothelial cells at the sprouting front, but elevated in non-proliferating endothelial cells at the termination zone of angiogenesis, presumably serving to halt angiogenesis (189). Levels of endogenous VASH-2, a homologue of VASH-1 that is mainly derived from infiltrating mononuclear cells, are elevated at the sprouting front, but low at the termination zone of angiogenesis, serving to induce angiogenesis (189).